TY - JOUR A1 - Güsgen, C. A1 - Anger, F. A1 - Hauer, T. A1 - Willms, A. A1 - Buhr, H. J. A1 - Germer, C.-T. A1 - Schwab, R. A1 - Lock, J. F. T1 - Fortbildung von Allgemein- und Viszeralchirurgen in der lebensrettenden Notfallchirurgie. Ergebnisse einer Umfrage unter Operationskursteilnehmern JF - Der Chirurg N2 - Hintergrund Die geringe Anzahl operativ zu versorgender Körperhöhlenverletzungen erfordert ein Umdenken in der chirurgischen Aus- und Weiterbildung. Ein entsprechendes Kursformat wird seit 2014 über die DGAV angeboten. Um Berechtigung, Bedarf, Nutzen und Erfolg eines solchen Kursformates zu erheben, erfolgte eine Evaluation durch die bisherigen Kursteilnehmer. Material und Methoden Kursevaluation und zusätzliche Onlinebefragung der bisherigen Kursteilnehmer hinsichtlich Alter, Geschlecht, Ausbildungsstand, Fachrichtung, Versorgungsstufe des Krankenhauses, notfallchirurgischer Erfahrungen, der Häufigkeit chirurgischer Notfallversorgungen, Teilnahme an anderen Kursformaten, Erfahrungen nach der Kursteilnahme, Einschätzung der aktuellen Fort- und Weiterbildungssituation und Finanzierung solcher Kurse. Ergebnisse Insgesamt 142 Kursteilnehmer evaluierten ihre Kursteilnahme, zusätzlich beantworteten 83 den Onlinefragebogen. Über 90 % berichteten von einem nachhaltigen positiven Einfluss des Kurses auf ihr notfallchirurgisches Handeln. Mehr als die Hälfte konnte von konkreten Notfallsituationen berichten, die sie aufgrund der Kursteilnahme besser bewältigen konnten. In der Notfallversorgung erfahrene Chirurgen bewerteten den eigenen Lernerfolg durch die Kursteilnahme signifikant häufiger positiv als ihre weniger erfahrenen Kollegen. Keinen Einfluss auf den Lernerfolg hatten eine Ober- oder Chefarztposition, die Versorgungsstufe des Krankenhauses, das Alter oder Geschlecht der Teilnehmer. Die Mehrheit der antwortenden Chirurgen befürwortet die Integration eines solchen Kursformates in die chirurgische Weiterbildung und fordert hierzu eine finanzielle Unterstützung. Schlussfolgerung Kursformate, in denen notfallchirurgische Strategien und Fähigkeiten vermittelt werden, sind etabliert und werden sehr positiv evaluiert. Die Fort- und Weiterbildung in notfallchirurgischen Fähigkeiten und Kenntnissen liegt im gesellschaftlichen Interesse und zumindest anteilig auch in ihrer Verantwortung. N2 - Background Due to a decreasing number of emergency procedures for body cavity injuries, surgical training is inadequate and current educational concepts must be reconsidered. The German Society for General and Visceral Surgery has set up a surgical training course in 2014 to overcome this shortage. In order to assess the eligibility, needs, benefits and success of such a training format, participants were asked to evaluate the program. Material and methods All participants evaluated the course during participation and were later asked to answer an online survey regarding their age, gender, level of surgical education, surgical discipline, level of care of the hospital, emergency surgical experience and frequency of performing emergency surgery, participation in other programs, experiences after participating in the course, rating of the current training curriculum and funding of such courses. Results Out of 142 participants 83 replied to the online survey. Over 90% reported a lasting positive influence of the course on emergency surgical skills. More than half of the responders remembered a clinical situation which they successfully managed due to the skills they gained during the course. Surgeons experienced in emergency treatment felt significantly more benefit than less experienced colleagues. A consultancy position, the level of care of the hospital, age and sex of the participants did not influence the overall benefits reported. The majority of responding surgeons were in favor of including such a training course in surgical education and stipulated public financial support. Conclusion Course formats that mediate emergency surgery strategies and skills are established and well accepted. Training of surgeons in life-saving emergency surgery is in the public interest and is also partly the responsibility of society. T2 - Advanced training of general and visceral surgeons in life-saving emergency surgery. Results of a survey among participants of a surgery course KW - Damage control surgery KW - Terroranschlagtrauma KW - Abdominaltrauma KW - Messerstichverletzung KW - Schussverletzung KW - damage control surgery KW - terror attack trauma KW - abdominal trauma KW - stab wounds KW - shooting injuries Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235246 SN - 0009-4722 VL - 91 ER - TY - JOUR A1 - Brand, Markus A1 - Reimer, Stanislaus A1 - Reibetanz, Joachim A1 - Flemming, Sven A1 - Kornmann, Marko A1 - Meining, Alexander T1 - Endoscopic full thickness resection vs. transanal endoscopic microsurgery for local treatment of rectal neuroendocrine tumors - a retrospective analysis JF - International Journal of Colorectal Disease N2 - Purpose Local treatment of small well-differentiated rectal neuroendocrine tumors (NETs) is recommended by current guidelines. However, although several endoscopic methods have been established, the highest R0 rate is achieved by transanal endoscopic microsurgery (TEM). Since a recently published study about endoscopic full thickness resection (eFTR) showed a R0 resection rate of 100%, the aim of this study was to evaluate both methods (eFTR vs. TEM). Methods We retrospectively analyzed all patients with rectal NET treated either by TEM (1999–2018) or eFTR (2016–2019) in two tertiary centers (University Hospital Wuerzburg and Ulm). We analyzed clinical, procedural, and histopathological outcomes in both groups. Results Twenty-eight patients with rectal NET received local treatment (TEM: 13; eFTR: 15). Most tumors were at stage T1a and grade G1 or G2 (in the TEM group two G3 NETs were staged T2 after neoadjuvant chemotherapy). In both groups, similar outcomes for en bloc resection rate, R0 resection rate, tumor size, or specimen size were found. No procedural adverse events were noted. Mean procedure time in the TEM group was 48.9 min and 19.2 min in the eFTR group. Conclusion eFTR is a convincing method for local treatment of small rectal NETs combining high safety and efficacy with short interventional time. KW - rectum KW - neuroendocrine tumor (NET) KW - transanal endoscopic microsurgery (TEM) KW - endoscopic full thickness resection (eFTR) KW - full-thickness resection device (FTRD) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234833 SN - 0179-1958 VL - 36 ER - TY - JOUR A1 - Glaser, Kirsten A1 - Kern, David A1 - Speer, Christian P. A1 - Schlegel, Nicolas A1 - Schwab, Michael A1 - Thome, Ulrich H. A1 - Härtel, Christoph A1 - Wright, Clyde J. T1 - Imbalanced inflammatory responses in preterm and term cord blood monocytes and expansion of the CD14\(^+\)CD16\(^+\) subset upon toll-like receptor stimulation JF - International Journal of Molecular Sciences N2 - Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point to generally impaired TLR signaling, others to differences in individual pathways. In the present study, we assessed mRNA and protein expression of pro- and anti-inflammatory cytokines in preterm and term cord blood (CB) monocytes compared with adult controls stimulated ex vivo with Pam3CSK4, zymosan, polyinosinic:polycytidylic acid, lipopolysaccharide, flagellin, and CpG oligonucleotide, which activate the TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 pathways, respectively. In parallel, frequencies of monocyte subsets, stimulus-driven TLR expression, and phosphorylation of TLR-associated signaling molecules were analyzed. Independent of stimulus, pro-inflammatory responses of term CB monocytes equaled adult controls. The same held true for preterm CB monocytes—except for lower IL-1β levels. In contrast, CB monocytes released lower amounts of anti-inflammatory IL-10 and IL-1ra, resulting in higher ratios of pro-inflammatory to anti-inflammatory cytokines. Phosphorylation of p65, p38, and ERK1/2 correlated with adult controls. However, stimulated CB samples stood out with higher frequencies of intermediate monocytes (CD14\(^+\)CD16\(^+\)). Both pro-inflammatory net effect and expansion of the intermediate subset were most pronounced upon stimulation with Pam3CSK4 (TLR1/2), zymosan (TR2/6), and lipopolysaccharide (TLR4). Our data demonstrate robust pro-inflammatory and yet attenuated anti-inflammatory responses in preterm and term CB monocytes, along with imbalanced cytokine ratios. Intermediate monocytes, a subset ascribed pro-inflammatory features, might participate in this inflammatory state. KW - neonatal immunology KW - inflammation KW - preterm infants KW - monocytes KW - cord blood KW - monocyte subsets KW - cytokines KW - Toll-like receptor signaling Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311056 SN - 1422-0067 VL - 24 IS - 5 ER - TY - JOUR A1 - Griebsch, Nora-Isabell A1 - Kern, Johanna A1 - Hansen, Jonas A1 - Rullmann, Michael A1 - Luthardt, Julia A1 - Helfmeyer, Stephanie A1 - Dekorsy, Franziska J. A1 - Soeder, Marvin A1 - Hankir, Mohammed K. A1 - Zientek, Franziska A1 - Becker, Georg-Alexander A1 - Patt, Marianne A1 - Meyer, Philipp M. A1 - Dietrich, Arne A1 - Blüher, Matthias A1 - Ding, Yu-Shin A1 - Hilbert, Anja A1 - Sabri, Osama A1 - Hesse, Swen T1 - Central serotonin/noradrenaline transporter availability and treatment success in patients with obesity JF - Brain Sciences N2 - Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [\(^{11}\)C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [\(^{11}\)C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m\(^2\)) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes. KW - obesity KW - serotonin KW - noradrenaline KW - serotonin transporter KW - noradrenaline transporter KW - Roux-en-Y gastric bypass surgery KW - body mass index (BMI; kg/m\(^2\)) KW - radiotracer KW - PET KW - PET imaging Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290294 SN - 2076-3425 VL - 12 IS - 11 ER - TY - JOUR A1 - Kelm, Matthias A1 - Reibetanz, Joachim A1 - Kim, Mia A1 - Schoettker, Kathrin A1 - Brand, Markus A1 - Meining, Alexander A1 - Germer, Christoph-Thomas A1 - Flemming, Sven T1 - Kono-S anastomosis in Crohn’s disease: A retrospective study on postoperative morbidity and disease recurrence in comparison to the conventional side-to-side anastomosis JF - Journal of Clinical Medicine N2 - Introduction: The rates of postoperative recurrence following ileocecal resection due to Crohn’s disease remain highly relevant. Despite this fact, while the Kono-S anastomosis technique initially demonstrated promising results, robust evidence is still lacking. This study aimed to analyze the short- and long-term outcomes of the Kono-S versus side-to-side anastomosis. Methods: A retrospective single-center study was performed including all patients who received an ileocecal resection between 1 January 2019 and 31 December 2021 at the Department of Surgery at the University Hospital of Wuerzburg. Patients who underwent conventional a side-to-side anastomosis were compared to those who received a Kono-S anastomosis. The short- and long-term outcomes were analyzed for all patients. Results: Here, 29 patients who underwent a conventional side-to-side anastomosis and 22 patients who underwent a Kono-S anastomosis were included. No differences were observed regarding short-term postoperative outcomes. The disease recurrence rate postoperatively was numerically lower following the Kono-S anastomosis (median Rutgeert score of 1.7 versus 2.5), with a relevantly increased rate of patients in remission (17.2% versus 31.8%); however, neither of these results reached statistical significance. Conclusion: The Kono-S anastomosis method is safe and feasible and potentially decreases the severity of postoperative disease remission. KW - Crohn’s disease KW - surgical therapy KW - ileocecal resection KW - Kono-S anastomosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297334 SN - 2077-0383 VL - 11 IS - 23 ER - TY - JOUR A1 - Curtaz, Carolin J. A1 - Schmitt, Constanze A1 - Herbert, Saskia-Laureen A1 - Feldheim, Jonas A1 - Schlegel, Nicolas A1 - Gosselet, Fabien A1 - Hagemann, Carsten A1 - Roewer, Norbert A1 - Meybohm, Patrick A1 - Wöckel, Achim A1 - Burek, Malgorzata T1 - Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood-brain barrier model JF - Fluids and Barriers of the CNS N2 - Background The most threatening metastases in breast cancer are brain metastases, which correlate with a very poor overall survival, but also a limited quality of life. A key event for the metastatic progression of breast cancer into the brain is the migration of cancer cells across the blood-brain barrier (BBB). Methods We adapted and validated the CD34\(^+\) cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) to analyse the effects of patient serum on BBB properties. We collected serum samples from healthy donors, breast cancer patients with primary cancer, and breast cancer patients with, bone, visceral or cerebral metastases. We analysed cytokine levels in these sera utilizing immunoassays and correlated them with clinical data. We used paracellular permeability measurements, immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro. Results The BLECs cultured together with brain pericytes in transwells developed a tight monolayer with a correct localization of claudin-5 at the tight junctions (TJ). Several BBB marker proteins such as the TJ proteins claudin-5 and occludin, the glucose transporter GLUT-1 or the efflux pumps PG-P and BCRP were upregulated in these cultures. This was accompanied by a reduced paracellular permeability for fluorescein (400 Da). We then used this model for the treatment with the patient sera. Only the sera of breast cancer patients with cerebral metastases had significantly increased levels of the cytokines fractalkine (CX3CL1) and BCA-1 (CXCL13). The increased levels of fractalkine were associated with the estrogen/progesterone receptor status of the tumour. The treatment of BLECs with these sera selectively increased the expression of CXCL13 and TJ protein occludin. In addition, the permeability of fluorescein was increased after serum treatment. Conclusion We demonstrate that the CD34\(^+\) cell-derived human in vitro BBB model can be used as a tool to study the molecular mechanisms underlying cerebrovascular pathologies. We showed that serum from patients with cerebral metastases may affect the integrity of the BBB in vitro, associated with elevated concentrations of specific cytokines such as CX3CL1 and CXCL13. KW - Metastatic breast cancer KW - Blood–brain barrier KW - In vitro models KW - CX3CL1 KW - CXCL13 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229940 VL - 17 ER - TY - JOUR A1 - Flemming, S. A1 - Hankir, M. A1 - Ernestus, R.-I. A1 - Seyfried, F. A1 - Germer, C.-T. A1 - Meybohm, P. A1 - Wurmb, T. A1 - Vogel, U. A1 - Wiegering, A. T1 - Surgery in times of COVID-19 — recommendations for hospital and patient management JF - Langenbeck's Archives of Surgery N2 - Background The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), has escalated rapidly to a global pandemic stretching healthcare systems worldwide to their limits. Surgeonshave had to immediately react to this unprecedented clinical challenge by systematically repurposing surgical wards. Purpose To provide a detailed set of guidelines developed in a surgical ward at University Hospital Wuerzburg to safelyaccommodate the exponentially rising cases of SARS-CoV-2 infected patients without compromising the care of emergencysurgery and oncological patients or jeopardizing the well-being of hospital staff. Conclusions The dynamic prioritization of SARS-CoV-2 infected and surgical patient groups is key to preserving life whilemaintaining high surgical standards. Strictly segregating patient groups in emergency rooms, non-intensive care wards andoperating areas prevents viral spread while adequately training and carefully selecting hospital staff allow them to confidentlyand successfully undertake their respective clinical duties. KW - SARS-CoV-2 KW - COVID-19 KW - Surgery Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231766 SN - 1435-2443 VL - 405 ER - TY - JOUR A1 - Notz, Quirin A1 - Schmalzing, Marc A1 - Wedekink, Florian A1 - Schlesinger, Tobias A1 - Gernert, Michael A1 - Herrmann, Johannes A1 - Sorger, Lena A1 - Weismann, Dirk A1 - Schmid, Benedikt A1 - Sitter, Magdalena A1 - Schlegel, Nicolas A1 - Kranke, Peter A1 - Wischhusen, Jörg A1 - Meybohm, Patrick A1 - Lotz, Christopher T1 - Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome—An Observational Pilot Study JF - Frontiers in Immunology N2 - Objectives The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS). Methods This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14th and May 28th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed. Results All patients suffered from severe ARDS, 30.8% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and naïve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment. Conclusions Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience. KW - Coronavirus Disease 2019 KW - acute respiratory distress syndrome KW - Severe Acute Respiratory Syndrome Coronavirus 2 KW - cytokines KW - inflammation KW - growth differentiation factor 15 KW - immune response Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212815 SN - 1664-3224 VL - 11 ER - TY - THES A1 - Knop, Juna-Lisa T1 - Untersuchungen zur Bedeutung von Spaltprodukten des vaskulär endothelialen (VE-) Cadherin als Auslöser für die Schrankenstörung des Gefäßendothels T1 - Characterisation of the endothelial barrier-disruptive effects of soluble vascular endothelial (sVE-) cadherin N2 - Ein Schlüsselereignis, welches dem prognosebestimmenden Organversagen bei systemi-schen Entzündungsprozessen und Sepsis vorangeht, ist die Entwicklung einer mikrovas-kulären endothelialen Schrankenstörung. Das vaskuläre endotheliale (VE-) Cadherin als mechanischer Stabilisator der Endothelbarriere spielt dabei eine wichtige Rolle. In der Inflammation werden Spaltprodukte von VE-Cadherin (sVE-Cadherin) gebildet. Ge-genstand der vorliegenden Arbeit war die Untersuchung der Hypothese ob diese Spalt-produkte selbst an der Störung der endothelialen Barrierefunktion beteiligt sind. Es wurde hierfür humanes sVE-Cadherin bestehend aus den extrazellulären Domänen EC1-5 (sVE-CadherinEC1-5) generiert. In Messungen des transendothelialen elektrischen Widerstands (TER), mit Immunfluoreszenzfärbungen und Western Blot Analysen wird gezeigt, dass sVE-Cadherin dosisabhängig die Barriere Integrität in primären humanen dermalen Endothelzellen stört. Dies führt zu einer Reduktion von VE-Cadherin und den assoziierten Proteinen α-, γ- und δ-Catenin und ZO-1, die nach der Applikation von sVE-Cadherin an den Zellgrenzen reduziert sind. Die Interaktion zwischen VE-PTP und VE-Cadherin wird durch sVE-CadherinEC1-5 reduziert. Durch pharmakologische Hem-mung der Phosphataseaktivität von VE-PTP mittels AKB9778 wird der durch sVE-CadherinEC1-5-induzierte Verlust der Endothelbarriere aufgehoben. Dagegen zeigt die direkte Aktivierung von Tie-2 mittels Angiopoetin-1 keinen protektiven Effekt auf die durch sVE-CadherinEC1-5 gestörte Endothelbarriere. Weitere Analysen zeigen eine erhöh-te Expression von GEF-H1 durch sVE-CadherinEC1-5. Diese ist ebenfalls durch AKB9778 hemmbar. Zusätzlich zu diesen Untersuchungen wurden die Konstrukte EC1-4 und EC3-5 in ver-schiedene Vektoren kloniert, um zu bestimmen, ob die extrazelluläre Domäne 5 von VE-Cadherin die dominante Rolle bei den sVE-Cadherin-vermittelten Effekten spielt. Zusammenfassend zeigen diese Untersuchungen zum ersten Mal, dass sVE-CadherinEC1-5 unabhängig von proinflammatorischen Auslösern über die Aktivierung des VE-PTP/RhoA-Signalweges den Zusammenbruch der Endothelbarriere mitversursacht. Dies stellt einen neuen pathophysiologischer Mechanismus dar, der zum Gesamtverständnis der entzündungsinduzierten Barriereveränderungen des Endothels beiträgt. N2 - A key prognostic event preceding organ failure in sepsis and systemic inflammatory pro-cesses is dysfunction of the microvascular endothelial barrier. The transmembrane pro-tein vascular endothelial (VE-) cadherin is an important prerequisite to stabilize endothe-lial barrier. VE-cadherin is cleaved under inflammatory conditions which results in the release of soluble VE-cadherin (sVE-cadherin). The main hypothesis of this thesis is to investigate whether sVE-cadherin itself directly disrupts the endothelial barrier in the absence of proinflammatory stimuli. Human sVE-cadherin consisting of extracellular domains EC1-5 (sVE-cadherinEC1-5) was generated and applied onto primary human dermal endothelial cells (HDMECs) for structural and functional analysis. Measurements of transendothelial electrical resistance (TER) and 4 kDa FITC-dectran flux revealed that sVE-cadherinEC1-5 dose-dependently disrupts endothelial barrier integrity. This was confirmed by immunostaining and im-munoblotting analysis which showed that sVE-cadherinEC1-5 treatment reduced overall levels of VE-cadherin and the associated proteins α-, γ- and δ-catenin and ZO-1 as well as their distribution at the cell border of HDMECs. sVE-cadherinEC1-5 treatment reduced the interaction between the phosphatase VE-PTP and VE-cadherin. Accordingly, phar-macological inhibition of VE-PTP using AKB9778 reversed sVE-cadherinEC1-5-induced endothelial barrier loss. Further analysis showed that the increased expression of GEF-H1 by sVE-cadherinEC1-5 is also attenuated by AKB9778. In addition to these studies, the constructs EC1-4 and EC3-5 were cloned into different vectors to determine wheth-er the extracellular domain 5 of VE-cadherin plays the dominant role in sVE-cadherin-mediated effects. In summary, these studies show for the first time that sVE-cadherinEC1-5 actively con-tributes to breakdown of the endothelial barrier independently of proinflammatory stim-uli via activation of the VE-PTP/RhoA signaling pathway. This represents a new patho-physiological mechanism that adds to the understanding of inflammation-induced endo-thelial barrier changes. KW - Endothel KW - Sepsis KW - Cadherine KW - Proteintyrosinphosphatase KW - Rho-Kinasen KW - VE-Cadherin KW - VE-PTP KW - RhoA KW - ve-cadherin Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-344687 ER - TY - JOUR A1 - Schmitz, Sophia M. A1 - Storms, Sebastian A1 - Koch, Alexander A1 - Stier, Christine A1 - Kroh, Andreas A1 - Rheinwalt, Karl P. A1 - Schipper, Sandra A1 - Hamesch, Karim A1 - Ulmer, Tom F. A1 - Neumann, Ulf P. A1 - Alizai, Patrick H. T1 - Insulin resistance is the main characteristic of metabolically unhealthy obesity (MUO) associated with NASH in patients undergoing bariatric surgery JF - Biomedicines N2 - (1) Background: Metabolically healthy obesity (MHO) is a concept that applies to obese patients without any elements of metabolic syndrome (metS). In turn, metabolically unhealthy obesity (MUO) defines the presence of elements of metS in obese patients. The components of MUO can be divided into subgroups regarding the elements of inflammation, lipid and glucose metabolism and cardiovascular disease. MUO patients appear to be at greater risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) compared to MHO patients. The aim of this study was to evaluate the influence of different MUO components on NAFLD and NASH in patients with morbid obesity undergoing bariatric surgery. (2) Methods: 141 patients undergoing bariatric surgery from September 2015 and October 2021 at RWTH Aachen university hospital (Germany) were included. Patients were evaluated pre-operatively for characteristics of metS and MUO (HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension). Intraoperatively, a liver biopsy was taken from the left liver lobe and evaluated for the presence of NAFLD or NASH. In ordinal regression analyses, different factors were evaluated for their influence on NAFLD and NASH. (3) Results: Mean BMI of the patients was 52.3 kg/m\(^2\) (36–74.8, SD 8.4). Together, the parameters HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension accounted for a significant amount of variance in the outcome, with a likelihood ratio of χ\(^2\) (9) = 41.547, p < 0.001, for predicting the presence of NASH. Only HOMA was an independent predictor of NASH (B = 0.102, SE = 0.0373, p = 0.007). Evaluation of steatosis showed a similar trend (likelihood ratio χ\(^2\) (9) = 40.272, p < 0.001). Independent predictors of steatosis were HbA1c (B = 0.833, SE = 0.343, p = 0.015) and HOMA (B = 0.136, SE = 0.039, p < 0.001). (4) Conclusions: The above-mentioned model, including components of MUO, was significant for diagnosing NASH in patients with morbid obesity undergoing bariatric surgery. Out of the different subitems, HOMA independently predicted the presence of NASH and steatosis, while HbA1c independently predicted steatosis and fibrosis. Taken together, the parameter of glucose metabolism appears to be more accurate for the prediction of NASH than the parameters of lipid metabolism, inflammation or the presence of cardiovascular disease. KW - NAFLD KW - metabolically unhealthy obesity KW - obesity surgery KW - insulin resistance Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319213 SN - 2227-9059 VL - 11 IS - 6 ER -